Online newspaper of professor Yasser Metwally

I am professor Yasser Metwally, professor of neurology, Ain Shams university, Cairo, Egypt, Visit my web site at: http://yassermetwally.com

This post contains simple medical information to neurological patients (vist my site at http://patients.yassermetwally.com)

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INTRODUCTION

Intracranial tumors may involve the brain or other structures (eg, cranial nerves, meninges). Brain tumors are found in about 2% of routine autopsies. The tumors usually develop during early or middle adulthood but may develop at any age; they are becoming more common among the elderly. Some tumors are benign, but because the cranial vault allows no room for expansion, even these tumors can be serious.

• Classification

Some primary intracranial tumors (eg, gliomas, medulloblastomas, ependymomas) originate in brain parenchyma; others (eg, meningiomas, acoustic neuromas, other schwannomas) originate in extraneural structures. Extracranial tumors may metastasize to any intracranial structure or to the skull. In the brain, metastases are about 10 times more common than primary tumors.

BRAIN METASTASES

Type of tumor varies somewhat by site and patient age. In children, common primary tumors are cerebellar astrocytomas and medulloblastomas, ependymomas, gliomas of the brain stem or optic nerve, germinomas, and congenital tumors. Congenital tumors include craniopharyngiomas, chordomas, germinomas, teratomas, dermoid cysts, angiomas, and hemangioblastomas. The most common metastatic tumors in children are neuroblastoma (usually epidural) and leukemia (meningeal).

In adults, common primary tumors include meningiomas, schwannomas, primary lymphomas, and gliomas of the cerebral hemispheres (particularly glioblastoma multiforme and anaplastic astrocytoma, which are malignant, and astrocytoma and oligodendroglioma, which are more benign). In adults, the most common sources of metastases are bronchogenic carcinoma, adenocarcinoma of the breast, malignant melanoma, and any cancer that has spread to the lungs; however, any metastatic cancer can spread to the brain.

• Pathophysiology

Neurologic dysfunction may result from tumor invasion and destruction of brain tissue, from direct compression of adjacent tissue by the tumor, or, rarely, from paraneoplastic syndromes . Neurologic dysfunction can also result from increased intracranial pressure (which may develop because of the space occupied by the tumor), cerebral edema, obstructed dural venous sinuses (especially by bony or extradural metastatic tumors), obstructed CSF drainage (occurring early with 3rd ventricle or posterior fossa tumors), or obstructed CSF absorption (eg, when leukemia or carcinoma involves the meninges). A malignant tumor can develop new internal blood vessels, which can bleed or become occluded, resulting in necrosis; either problem can cause neurologic dysfunction that mimics stroke.

Benign tumors grow slowly. They may become quite large before causing symptoms, partly because often there is no cerebral edema. Malignant tumors grow rapidly but rarely spread beyond the CNS. Death results from local tumor growth and thus can result from benign as well as malignant tumors. Therefore, distinguishing between benign and malignant is prognostically less important for brain tumors.

• Symptoms and Signs

Many symptoms result from increased intracranial pressure. The most common is headache. Headache may be most intense when patients awake from deep non-REM sleep (usually several hours after falling asleep) because hypoventilation, which increases cerebral blood flow and thus intracranial pressure, is usually maximal during non-REM sleep. When intracranial pressure is very high, the headache may be accompanied by vomiting, which may occur with little preceding nausea. Papilledema develops in about 25% of patients with a brain tumor but may be absent even if intracranial pressure is increased. In infants and very young children, increased intracranial pressure may enlarge the head. If intracranial pressure increases sufficiently, brain herniation occurs.

Deterioration in mental status is the 2nd most common symptom. Manifestations include drowsiness, lethargy, personality changes, disordered conduct, and impaired cognition, particularly with malignant brain tumors. Generalized seizures may occur, more often with primary than metastatic brain tumors. Impaired consciousness can result from herniation, brain stem dysfunction, or diffuse bilateral cortical dysfunction. Airway reflexes may be impaired.

Some symptoms may result from focal brain dysfunction. Focal neurologic deficits, endocrine dysfunction, or focal seizures (sometimes with secondary generalization) may develop depending on the tumor’s location. Focal symptoms and signs often suggest the tumor’s location. However, sometimes focal deficits do not correspond to the tumor’s location. An example of these deficits, called false localizing signs, is unilateral or bilateral lateral rectus palsy; it causes paresis of eye abduction due to increased intracranial pressure compressing the 6th cranial nerve, ipsilateral hemiplegia due to compression of the contralateral cerebral peduncle against the tentorium (Kernohan’s notch), and ipsilateral visual field defect due to ischemia in the contralateral occipital lobe.

Some tumors cause meningeal inflammation, resulting in subacute or chronic meningitis.

• Diagnosis

Early-stage brain tumors are often misdiagnosed. A brain tumor should be considered in patients with progressive focal or global brain neurologic deficits; new seizures; persistent, unexplained, recent-onset headaches, particularly if worsened by sleep; or evidence of increased intracranial pressure (eg, papilledema, unexplained vomiting). Similar findings can result from other intracranial masses (eg, abscess, aneurysm, arteriovenous malformation, intracerebral hemorrhage, subdural hematoma, granuloma, parasitic cysts such as neurocysticercosis) or ischemic stroke. Tumors should also be considered as causes in patients with a pituitary or hypothalamic endocrinopathy.

A complete neurologic examination, neuroimaging, and chest x-rays (for a source of metastases) should be done. T1-weighted MRI with gadolinium is the study of choice. CT with contrast agent is an alternative. MRI usually detects low-grade astrocytomas and oligodendrogliomas earlier than CT and shows brain structures near bone (eg, the posterior fossa) more clearly. If whole-brain imaging does not show sufficient detail in the target area (eg, sella turcica, cerebellopontine angle, optic nerve), closely spaced images or other special views of the area are obtained. If neuroimaging is normal but increased intracranial pressure is suspected, idiopathic intracranial hypertension should be considered and lumbar puncture performed.

Radiographic clues to the type of tumor, mainly location and pattern of enhancement on MRI, may be inconclusive; brain biopsy may be required. Specialized tests (eg, molecular and genetic tumor markers in blood and CSF) can help in some cases: In patients with AIDS, Epstein-Barr virus titers in CSF typically increase as CNS lymphoma develops.

• Treatment

Patients with coma or impaired airway reflexes require endotracheal intubation. Brain herniation due to tumors is treated with mannitol 25 to 100 g infused IV, a corticosteroid (eg, dexamethasone)

Treatment of the brain tumor depends on pathology and location. Surgical excision should be used for diagnosis and symptom relief. It may cure benign tumors. For tumors infiltrating the brain parenchyma, treatment is multimodal. Radiation therapy is required, and chemotherapy appears to benefit some patients.

Treatment of metastatic tumors includes radiation therapy and sometimes stereotactic radiosurgery. For patients with a solitary metastasis, surgical excision of the tumor before radiation therapy improves outcome.

• Radiation Therapy and Neurotoxicity

Radiation therapy may be directed diffusely to the whole head for diffuse or multicentric tumors or locally for well-demarcated tumors. Localized brain radiation therapy may be conformal, targeting the tumor with the aim of sparing normal brain tissue, or stereotactic, involving implantation of radioactive stable iodine (125I3) or iridium-192 (192Ir4), called brachytherapy, or use of a gamma knife or linear accelerator. Gliomas are treated with conformal radiation therapy; a gamma knife or linear accelerator is useful for metastases. Giving radiation daily tends to maximize efficacy and minimize damage to normal CNS tissue (neurotoxicity).

Degree of neurotoxicity depends on cumulative radiation dose, individual dose size, duration of therapy, volume of tissue irradiated, and individual susceptibility. Because susceptibility varies, prediction of radiation toxicity is imprecise. Symptoms of toxicity can develop in the 1st few days (acute) or months of treatment (early-delayed) or several months to years after treatment (late-delayed). Rarely, radiation causes gliomas, meningiomas, or peripheral nerve sheath tumors years after therapy.

Acute brain radiation toxicity in children and adults is characterized by headache, nausea, vomiting, somnolence, and sometimes worsening focal neurologic signs. It is particularly likely if intracranial pressure is high. Using corticosteroids to lower intracranial pressure can prevent or treat acute toxicity. Acute toxicity lessens with subsequent treatments.

Early-delayed brain toxicity can cause an encephalopathy in children or adults that must be distinguished from worsening or recurrent brain tumor by MRI or CT. It occurs in children who have received prophylactic whole-brain radiation therapy for leukemia; they develop somnolence, which lessens spontaneously over several days to weeks, possibly more rapidly if corticosteroids are used. After radiation therapy to the neck or upper thorax, early-delayed toxicity can result in a myelopathy, characterized by Lhermitte’s sign (an electric shock–like sensation radiating down the back and into the legs when the neck is flexed). The myelopathy resolves spontaneously.

Late-delayed toxicity develops in most children and adults who receive diffuse brain radiation therapy if they survive long enough. The most common cause in children is diffuse therapy given to prevent leukemia or to treat medulloblastoma. After diffuse therapy, the main symptom is progressive dementia; many adults also develop an unsteady gait. MRI or CT shows cerebral atrophy. Toxicity after localized therapy more often involves focal neurologic deficits. MRI or CT shows a mass that may be enhanced by contrast agent and that may be difficult to distinguish from recurrence of the primary tumor. Excisional biopsy of the mass is diagnostic and often ameliorates symptoms.

After radiation therapy for extraspinal tumors (eg, due to Hodgkin lymphoma), late-delayed myelopathy can develop. It is characterized by progressive paresis and sensory loss, often as a Brown-Séquard syndrome (ipsilateral paresis and proprioceptive sensory loss, and contralateral loss of pain and temperature sensation). Most patients eventually become paraplegic.

GLIOMA

Gliomas are primary tumors that originate in brain parenchyma. Symptoms and diagnosis are similar to those of other brain tumors. Treatment involves surgical excision, radiation therapy, and, for some tumors, chemotherapy. Excision rarely cures.

Gliomas include astrocytomas, oligodendrogliomas, medulloblastomas, and ependymomas. Many gliomas infiltrate brain tissue diffusely and irregularly.

Astrocytomas are the most common gliomas. They are classified, in ascending order of malignancy, as grade 1 or 2 (low-grade astrocytomas), grade 3 (anaplastic astrocytomas), or grade 4 (glioblastomas, including glioblastoma multiforme, the most malignant). Low-grade or anaplastic astrocytomas tend to develop in younger patients and can evolve into glioblastomas (secondary glioblastomas). Glioblastomas contain chromosomally heterogeneous cells. They can develop de novo (primary glioblastomas), usually in middle-aged or elderly people. Primary and secondary glioblastomas have distinct genetic characteristics, which can change as the tumors evolve.

Figure 1. Supratentorial low-grade astrocytoma. (left) Sagittal Tl -weighted image shows well-circumscribed hypointense right parietal lobe mass. Axial T2-weighted (right) image show the mass to be hyperintense. There is no peritumoral edema. (Click to magnify figure)

Oligodendrogliomas are among the most benign gliomas. They affect mainly the cerebral cortex, particularly the frontal lobes.

Medulloblastomas develop mainly in children and young adults, usually near the 4th ventricle. Ependymomas are uncommon. They develop mainly in children, usually near the 4th ventricle. Medulloblastomas and ependymomas predispose to obstructive hydrocephalus.

Symptoms and signs vary by location . Diagnosis is the same as that of other brain tumors.

Figure 2. Optic chiasm glioma. Sagittal precontrast (left) and postcontrast (middle) Tl -weighted images show solid and cystic mass involving the optic chiasm. The solid portion enhances homogeneously. Axial intermediate-weighted image (right) shows hyperintense well-circumscribed optic chiasm mass. (Click to magnify figure)

• Treatment

Anaplastic astrocytomas and glioblastomas are treated with surgery, radiation therapy, and chemotherapy to reduce tumor mass. Excising as much tumor as possible is safe, prolongs survival, and improves neurologic function. After surgery, patients receive a full tumor dose (60 Gy) of radiation therapy; ideally, conformal radiation therapy, which targets the tumor and spares normal brain tissue, is used. Chemotherapy includes a nitrosourea.

Figure 3. Juvenile pilocytic astrocytoma. Sagittal Tl -weighted image (left) shows cerebellar hypointense mural nodule within a cyst. Sagittal post-contrast Tl -weighted image (middle) shows intense enhancement of the mural nodule. Axial T2-weighted image (right) shows hyperintense mural nodule within a cyst. The mural nodule contains multiple cystic foci. There is peritumoral edema. (Click to magnify figure)

Patients receiving chemotherapy require a CBC at varying intervals but at least 24 to 48 h before each chemotherapy session. Investigational therapies (eg, chemotherapy wafers, stereotactic radiosurgery, new chemotherapeutic drugs, gene or immune therapy) should also be considered. After conventional multimodal treatment, the survival rate for patients with anaplastic astrocytomas or glioblastomas is about 50% at 1 yr, 25% at 2 yr, and 10 to 15% at 5 yr. Prognosis is better if patients are 70%.

MENINGIOMA

Meningiomas are benign tumors of the meninges that can compress adjacent brain tissue. Symptoms depend on the tumor’s location. Diagnosis is by MRI with contrast agent. Treatment may include excision, stereotactic radiosurgery, and sometimes radiation therapy.

Meningiomas, particularly those < 2 cm in diameter, are among the most common intracranial tumors. Meningiomas are the only brain tumor more common among women. They tend to occur between ages 40 and 60 yr but can occur during childhood. These benign tumors can develop wherever there is dura, most commonly over the convexities near the venous sinuses, along the base of the skull, in the posterior fossa, and rarely within ventricles. Multiple meningiomas may develop. Meningiomas compress but do not invade brain parenchyma. They can invade and distort adjacent bone. There are many histologic types; all follow a similar clinical course, and some become malignant.

Symptoms depend on which part of the brain is compressed and thus on the tumor’s location. Midline tumors in the elderly can cause dementia with few other focal neurologic findings. Diagnosis is similar to that of other brain tumors, usually by MRI with a paramagnetic contrast agent. Bony abnormalities (eg, brain atrophy, hyperostosis around the cerebral convexities, changes in the tuberculum sellae) may be seen incidentally on CT or plain x-rays.

• Treatment

Asymptomatic meningiomas can be followed with serial neuroimaging. Symptomatic or enlarging meningiomas should be excised if possible. If they are large, encroach on blood vessels (usually surrounding veins), or are close to critical brain areas (eg, brain stem), surgery may cause more damage than the tumor and is thus deferred. Stereotactic radiosurgery is used for surgically inaccessible meningiomas and electively for other meningiomas. It is also used when tumor tissue remains after surgical excision or when the patient is elderly. If stereotactic radiosurgery is impossible or if a meningioma recurs, radiation therapy may be useful.

PINEAL REGION TUMORS

Pineal region tumors are usually germ cell tumors (eg, germinoma, choriocarcinoma, yolk-sac tumor, teratoma). Other primary pineal tumors include pineocytoma and the rare malignant pineoblastoma.

Pineal region tumors tend to occur during childhood but can occur at any age. They may increase intracranial pressure by compressing the aqueduct of Sylvius. They may also cause paresis of upward gaze, ptosis, and loss of pupillary light and accommodation reflexes by compressing the pretectum rostral to the superior colliculi. These tumors may cause precocious puberty, especially in boys, probably because the hypothalamus is compressed. Germinomas are the most common pineal region tumor.

Figure 4. Mixed germinomatous germ cell tumor. Axial Tl -weighted image (left) shows isointense pineal mass with small focus of bright signal representing hemorrhage. Axial T2-weighted image (middle) shows heterogeneous pineal mass. The dark signal foci likely represent calcification and hemorrhage. Sagittal postcontrast Tl -weighted image (right) shows fairly homogeneous enhancement. (Click to magnify figure)

CSF ß-human chorionic gonadotropin or a-fetoprotein may be elevated, depending on the tumor type. Elevated levels suggest the diagnosis; levels may be measured to monitor response to treatment. Prognosis and treatment depend on tumor histology. Radiation therapy, chemotherapy, radiosurgery, and surgery are used alone or in combination. Germinomas are very sensitive to radiation therapy and are often cured.

PITUITARY ADENOMA

Most pituitary tumors are adenomas. Symptoms include headache and endocrinopathies; endocrinopathies result when the tumor produces hormones or destroys hormone-producing tissue. Diagnosis is by MRI. Treatment includes surgery or radiation therapy and correction of any endocrinopathy.

Most tumors of the pituitary and suprasellar region are pituitary adenomas. Rarely, pituitary tumors are carcinomas. Meningiomas, craniopharyngiomas, metastases, and dermoid cysts may also develop in the region of the sella turcica.

Adenomas may be secretory or nonsecretory. Secretory adenomas produce pituitary hormones; many secretory adenomas are < 10 mm in size (microadenomas). Secretory adenomas can be classified by histologic staining characteristics (eg, acidophilic, basophilic, chromophobe [nonstaining]). The hormone produced often correlates with these characteristics; eg, acidophilic adenomas overproduce growth hormone, and basophilic adenomas overproduce ACTH. The hormone most commonly overproduced is prolactin.

Any tumor that grows out of the pituitary can compress optic nerve tracts, including the chiasm. Tumors may also compress or destroy pituitary or hypothalamic tissue, impairing hormone production or secretion.

• Symptoms and Signs

Headache may result from an enlarging pituitary adenoma, even when intracranial pressure is not increased. Visual manifestations such as bitemporal hemianopia, unilateral optic atrophy, and contralateral hemianopia may develop if a tumor compresses optic nerve tracts.

Many patients present with an endocrinopathy due to hormone deficiency or excess. Diabetes insipidus may develop if less vasopressin is released because the hypothalamus is compressed. Amenorrhea and galactorrhea in women and, less commonly, erectile dysfunction and gynecomastia in men may result from overproduction of prolactin. Gigantism before puberty or acromegaly after puberty may result from overproduction of growth hormone, and Cushing’s syndrome from overproduction of ACTH. Rarely, hemorrhage into a pituitary tumor causes pituitary apoplexy, with sudden headache, ophthalmoplegia, and visual loss.

• Diagnosis and Treatment

Pituitary tumors are suspected in patients with unexplained headaches, characteristic visual abnormalities, or endocrinopathies. Neuroimaging with 1-mm thick slices is done. MRI is usually much more sensitive than CT, particularly for microadenomas.

• Pituitary microadenoma

Endocrinopathies are treated. Pituitary tumors that secrete ACTH, growth hormone, or thyroid-stimulating hormone are surgically excised, usually using a transsphenoidal approach. Sometimes, particularly for surgically inaccessible or multifocal tumors, radiation therapy is required. Dopaminergic agonists (eg, bromocriptine)

PRIMARY CNS LYMPHOMA

Primary brain lymphomas originate in neural tissue and are usually B-cell tumors. Diagnosis requires neuroimaging and sometimes CSF analysis, Epstein-Barr titers, or brain biopsy. Treatment includes corticosteroids, chemotherapy, and radiation therapy.

Incidence of primary brain lymphomas is increasing, particularly among immunocompromised patients and the elderly. Lymphomas tend to infiltrate the brain diffusely, often as multicentric masses adjacent to the ventricles, but may occur as solitary brain masses. Lymphomas may also occur in the meninges, uvea, or vitreous humor. Most are B-cell tumors, often immunoblastic . The Epstein-Barr virus may contribute to development of lymphomas in immunocompromised patients. Most patients do not develop subsequent systemic lymphoma.

MRI can suggest the diagnosis. Neuroimaging may be unable to distinguish cerebral toxoplasmosis, which is common among patients with AIDS, from lymphoma. If there are meningeal signs, CSF is examined; it may contain lymphoma cells. In immunocompromised patients, Epstein-Barr virus DNA may be detected in CSF. If CSF does not contain lymphoma cells or Epstein-Barr virus DNA, guided-needle or open biopsy is required. Because lymphoma is initially highly sensitive to corticosteroids, giving these drugs just before biopsy may cause the lesion to disappear, resulting in a false-negative biopsy.

Most primary brain lymphomas are difficult to cure because they infiltrate the brain diffusely. Treatment includes corticosteroids, chemotherapy, and radiation therapy. Many chemotherapy regimens, particularly those containing methotrexate can also be delivered intrathecally. It is sometimes infused into the carotid artery after general anesthesia is induced and 25% mannitol is given IV to open the blood-brain barrier. Most chemotherapy regimens are followed by radiation therapy, usually after 12 to 16 wk but sometimes delayed until the tumor recurs to reduce radiation toxicity.

SPINAL CORD TUMOURS

Spinal cord tumors may develop within the spinal cord parenchyma, directly destroying tissue, or outside the cord parenchyma, often compressing the cord or nerve roots. Symptoms include progressive back pain and neurologic deficits referable to the spinal cord or spinal nerve roots. Diagnosis is by MRI. Treatment may include corticosteroids, surgical excision, and radiation therapy.

Spinal cord tumors may be intramedullary (within the cord parenchyma) or extramedullary (outside the parenchyma). The most common intramedullary tumors are gliomas (eg, ependymomas, low-grade astrocytomas). Extramedullary tumors may be intradural or extradural. Most intradural tumors are benign, usually meningiomas and neurofibromas, which are the most common primary spinal tumors. Most extradural tumors are metastatic, usually from carcinomas of the lung, breasts, prostate, kidneys, or thyroid or from lymphoma (eg, Hodgkin lymphoma, lymphosarcoma, reticulum cell sarcoma).

Intramedullary tumors infiltrate and destroy cord parenchyma and may extend over multiple spinal cord segments; an intramedullary tumor may result in a syrinx. Intradural and extradural tumors cause neurologic damage by compressing the spinal cord or nerve roots. Most extradural tumors invade and destroy bone before compressing the cord.

• Symptoms and Signs

Pain is an early symptom. It is progressive, unrelated to activity, and worsened by recumbency. Pain may occur in the back, radiate along the sensory distribution of a particular dermatome (radicular pain), or both. Usually, neurologic deficits referable to the spinal cord eventually develop. Common examples are spastic weakness, incontinence, and dysfunction of some or all of the sensory tracts at a particular segment of the spinal cord and below. Deficits are usually bilateral.

Many patients with extramedullary tumors present with pain, but some present with sensory deficits of the distal lower extremities or segmental neurologic deficits and spinal cord compression. Symptoms of spinal cord compression tend to worsen rapidly because most extradural tumors are metastatic. Symptoms of nerve root compression are also common; they include pain and paresthesias followed by sensory loss, muscular weakness, and, if compression is chronic, wasting, which occurs along the distribution of the affected roots.

• Diagnosis and Treatment

Spinal tumors are suggested by progressive, unexplained, or nocturnal back or radicular pain; segmental neurologic deficits; or unexplained neurologic deficits referable to the spinal cord or nerve roots. They are also suggested by unexplained back pain in patients with primary tumors of the lungs, breasts, prostate, kidneys, or thyroid or with lymphoma. Diagnosis is by MRI of the affected area of the spinal cord. CT is an alternative but is less accurate. Patients with segmental neurologic deficits or suspected spinal cord compression require emergency diagnosis and treatment.

If MRI does not show a spinal cord tumor, other spinal masses and paravertebral tumors are considered. Spinal x-rays, taken for other reasons, may show bone destruction, widening of the vertebral pedicles, or distortion of paraspinal tissues, especially if the tumor is metastatic.

For patients with neurologic deficits, corticosteroids (eg, dexamethasone , 50 mg IV, then 10 mg po qid) are begun immediately to reduce spinal cord edema and preserve function. Tumors compressing the spinal cord are treated as soon as possible. Some well-localized primary spinal cord tumors can be excised surgically. Deficits resolve in about 1/2 of these patients. For tumors that cannot be surgically excised, radiation therapy is used, with or without surgical decompression. Compressive metastatic extradural tumors are usually surgically excised from the vertebral body, then treated with radiation therapy. Noncompressive metastatic extradural tumors may be treated with radiation therapy alone but may require excision if radiation therapy is ineffective.

The author,

Professor Yasser Metwally